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Biomedical subjects

R Ismail

Publications and source records attributed to R Ismail.

At least 19 recordsLinked to original sources
PubMed2006

CYP2A6 polymorphisms in Malays, Chinese and Indians.

The genetically polymorphic cytochrome P450 (CYP) 2A6 is the major nicotine-oxidase in humans that may contribute to nicotine dependence and cancer susceptibility. The authors investigated the types and frequencies of CYP2A6 alleles in the three major ethnic groups in Malaysia and CYP2A6*1A, CYP2A6*1B, CYP2A6*1x2, CYP2A6*2, CYP2A6*3, CYP2A6*4, CYP2A6*5, CYP2A6*7, CYP2A6*8 and CYP2A6*10 were determined by allele-specific polymerase chain reaction (PCR) in 270 Malays, 172 Chinese and 174 Indians. Except for CYP2A6*2 and *3 that were not detected in the Malays and Chinese, all the other alleles were detected. Frequencies for the CYP2A6*4 allele were 7, 5 and 2%, respectively, in Malays, Chinese and Indians. A statistically significant high frequency of the duplicated CYP2A6*1x2 allele occurred among Chinese. Among Malays and Chinese, the most common allele was CYP2A6*1B, but it was CYP2A6*1A among Indians. These ethnic difference in frequencies suggested that further studies are required to investigate the implications on diseases such as cancer and smoking behaviour among these major ethnic groups in Malaysia.

Adult↗
PubMed2006

The relevance of CYP2D6 genetic polymorphism on chronic metoprolol therapy in cardiovascular patients.

BACKGROUND AND OBJECTIVE: CYP2D6 polymorphisms are well described in normal populations but there are few data on its clinical significance. We therefore investigated the influence of CYP2D6 polymorphism on steady-state plasma concentrations and apparent oral clearance of metoprolol in patients with cardiovascular diseases. METHODS: Ninety-one patients on metoprolol were recruited. Plasma concentrations of metoprolol and alpha-hydroxy metoprolol were measured at 4-h post-dose. CYP2D6 genotyping (*1, *3, *4, *5, *9, *8, *10, *17 and duplication) were performed on the DNA extracted. Ratio of plasma concentrations of metoprolol and alpha-hydroxy metoprolol and the apparent oral clearance of metoprolol were calculated. The influences of CYP2D6 genotypes were investigated. RESULTS: A 100-fold variation was noted for both plasma concentrations of metoprolol and alpha-hydroxy metoprolol. There was a weak correlation between the total daily doses and plasma concentrations of both. Plasma concentrations were found to be higher in patients with genotypes that predicted lower enzyme activity. One patient homozygous for CYP2D6*4 had the highest metoprolol concentration per unit dose. With an antimode of 10. Two patients were identified as poor metabolizers (PMs) (2.1%; 95% CI: 2.9). The PMs who had a plasma metabolic ratio (pMR) of 37.8 was homozygous CYP2D6*4 whereas the other with pMR 14.5 was genotyped CYP2D6 *4/*10. There was a 36-fold difference between the highest and lowest clearance values. Large overlaps in the clearance values were noted between most of the genotypes. CONCLUSIONS: Our data suggest that pharmacogenetic measures could be used to design a more individualized metoprolol dosage regimen for patients.

Adult↗
PubMed2006

Malaysian Indians are genetically similar to Caucasians: CYP2C9 polymorphism.

BACKGROUND: CYP2C9 is one of the major drug metabolizing enzymes for many drugs including warfarin, NSAIDs and losartan. It is polymorphic in many populations. Data on the distribution of CYP2C9 and the implication of CYP2C9 polymorphism in the Malaysian population is lacking. Our objectives were therefore to investigate the prevalence of CYP2C9 variants among unrelated healthy volunteers of Malays, Chinese and Indians in Malaysia. METHOD: Deoxyribonucleic acid was extracted using standard lysis methods. Allele specific polymerase chain reaction was performed for determination of CYP2C9*1, *2, *3, *4 and *5 variants according to Z. Zainuddin, L.K. Teh, A.W.M. Suhaimi, M.Z. Salleh, R. Ismail (2003, Clinica Chimica Acta, 336, 97). RESULT: The Chinese had the highest frequency of CYP2C9*1 (321/330, 97.27%), followed by the Malays and the Indians (402 of 420, 95.71% and 291 of 330, 88.18%, respectively). CYP2C9*2 was not found in the Chinese. CYP2C9*3 were detected in all the three races with the Indians having the highest frequency of CYP2C9*3 (9.7%). The Indians had a frequency of CYP2C9*2 and *3 similar to Tamilians and Caucasians. Two of the Indians had *2/*3 and one had *3/*3 genotypes and are likely to be slow metabolizers. No subject with CYP2C9*4 and *5 were detected in our populations. CONCLUSION: CYP2C9*2 and *3 were identified in our population. Indians are similar to Caucasians in terms of CYP2C9 genotypes and thus may respond to CYP2C9 substrates differently when compared with the Malays and Chinese in Malaysia.

Alleles↗
PubMed2006

An improved rapid genotyping method for the study of beta-2 adrenergic receptor gene polymorphisms using single tube allele specific multiplex PCR.

BACKGROUND: Seventeen single nucleotide polymorphisms (SNPs) have been identified so far, within the beta-2 receptor (beta(2) AR) gene. The presence of so many SNPs within the beta(2) AR gene causes a problem, for those studying beta(2) AR pharmacogenetics, in relation to which SNPs to choose. Most of the work has focused on the three common SNPs within the coding block (alleles 16, 27 and 164) and the techniques developed have been for these three functionally important alleles. OBJECTIVE: We report an improved polymerase chain reaction (PCR)-based method for the simultaneous detection of five functionally important beta(2) AR alleles, namely beta 16A/G, beta utr-20C/T, beta 27C/G, beta utr-47C/T and beta 164C/T. METHODS: Genomic DNA was used as a template for duplex and triplex PCR to detect the polymorphic sites of the five alleles. RESULT: DNA sequencing analysis confirmed the specificity of this PCR method. CONCLUSION: This simplified single-tube multiplexed PCR assay provides an easier, faster and more cost-effective method than those available for studying the specified polymorphisms of the beta(2)AR gene.

Genotype↗
PubMed2005

Genetic polymorphism of CYP2C8 in three Malaysian ethnics: CYP2C8*2 and CYP2C8*3 are found in Malaysian Indians.

BACKGROUND: CYP2C8 is genetically polymorphic. Four variants, CYP2C8*2, CYP2C8*3, CYP2C8*4 and CYP2C8*5, which contain mutations in the coding regions have been reported to exhibit different enzyme activity as compared with CYP2C8*1. OBJECTIVE: To determine the allele frequency of three codon-changing variants (CYP2C8*2, CYP2C8*3 and CYP2C8*4) in the Malaysian population. METHOD: Healthy unrelated volunteers from three major races in Malaysia were recruited. The study was approved by the local Research Ethics Committee. DNA was extracted using a standard protocol. A two-step multiplex PCR method was developed to detect three alleles of CYP2C8. PCR results were confirmed by subsequent direct DNA sequencing. RESULT: Only the Indians showed CYP2C8 polymorphism with allele frequency of 98% for CYP2C8*1, 0.8% for CYP2C8*2 and 1.2% for CYP2C8*3. CYP2C8*4 was not detected in any of the ethnic groups. CONCLUSION: To the best of our knowledge, the current study described, for the first time polymorphisms of CYP2C8 in Malaysian Indians.

Alleles↗
PubMed2004

A simple multiplex PCR method for the concurrent detection of three CYP2C8 variants.

BACKGROUND: Cytochrome P450 (CYP) 2C8 is a principle enzyme responsible for the metabolism of many clinically important drugs as well as endogenous compounds such as arachidonic acid. The enzyme is genetically polymorphic but a simple method is not available to study its genetic polymorphism. We developed and optimized a variant-specific PCR techniques to detect CYP2C8*2, CYP2C8*3 and CYP2C8*4. METHOD: Genomic DNA was extracted from blood using standard extraction methods. A two-step PCR method was developed to detect simultaneously three CYP2C8 variants. In the first PCR (PCR1), specific regions from exons 3, 5 and 8 of the CYP2C8 gene were amplified. The products were used as templates in parallel alleles-specific PCR (PCR2). This method was tested against DNA samples obtained from 57 healthy Malaysian volunteers. RESULT: The bands of interest were successfully amplified. This method showed specific and reproducible results when tested on healthy volunteers. DNA sequencing further confirmed genotype results obtained from current method. CONCLUSION: We have successfully developed and optimized a multiplex PCR method suitable for use in population studies of CYP2C8 polymorphism.

Alleles↗
PubMed2004

A simple and rapid genotyping method for beta-2 receptor (beta2 AR) gene using allele specific multiplex PCR.

BACKGROUND: Polymorphism of the beta2-adrenergic receptor (beta2 AR) gene is an important determinant of the function of this receptor. It affects receptor down-regulation and beta2-agonist responses. It has also been a focus of interest in attempts to elucidate the genetic basis of asthma, hypertension, obesity and cystic fibrosis. Several different techniques have been established to determine beta2 AR genotypes but none of these methods are simple enough to detect simultaneously all the five alleles of our research interest (Arg16/Gly16, -20T/C, Gln27/Glu27, -47T/C and Thr164/Ile164). OBJECTIVES: To develop a simple and rapid PCR based method for the simultaneous detection of five beta2 AR alleles. METHOD: DNA was extracted from whole blood using standard alkali lysis method. Primers specific at the 3' end for the polymorphic sites were designed. The nested allele specific PCR was optimized for reproducibility and specificity. Parameters investigated included concentrations of MgCl2, Taq polymerase, primers and annealing temperature, to produce specific bands of interest. DNA samples were selected at random and submitted for direct PCR sequencing. RESULT: The first PCR produced a fragment of size 710 bp, which was used as template for the subsequent duplex and triplex PCR to detect the mutation sites of the five alleles. The method was found reproducible and specific when used to genotype patients with bronchial asthma. The sequencing results confirmed the specificity of the PCR method. CONCLUSION: The simple and rapid method for the simultaneous detection of the five beta2 AR alleles is suitable for the study of beta2 polymorphism and its clinical consequences.

Alleles↗
PubMed2004

Relationship between Type A and B personality and debrisoquine hydroxylation capacity.

AIM: A person with Type A personality is an 'aggressor' compared with the rarely harried Type B. Although debrisoquine hydroxylase (CYP2D6) capacity has been associated with personality, no study has specifically investigated its association with personality Type A and B. Therefore the aim of this research was to study the impact of CYP2D6 on Type A and B personality. METHODS: Type A and B personality questionnaires were administered to 48 healthy patients undergoing elective orthopaedic surgery. After obtaining informed consent, patients were genotyped for the various CYP2D6 alleles by allele-specific polymerase chain reaction. Based on the genotypes, patients were grouped as extensive metabolizer (EM)1 (normal) (CYP2D6*1/*1), EM2 (intermediate) (CYP2D6*1/*4, CYP2D6*1/*5, CYP2D6*1/*9 and CYP2D6*1/*10) and EM3 (slow) (CYP2D6*4/*10, CYP2D6*5/*10, CYP2D6*10/*10 and CYP2D6*10/*17). Chi(2) was used to determine the relationship between the groups and personality types. RESULTS: The percentages of patients who were of the EM1, EM2 and EM3 groups were 20.8%, 52.1% and 27.1%, respectively. There was a significant difference (P = 0.032) between the three groups in terms of personality type, in which EM1 showed a tendency to be of personality Type A while EM2 and EM3 tended to be of personality Type B. CONCLUSION: The study suggests that there is a relationship between CYP2D6 activity and Type A and B personality.

Adolescent↗
PubMed2004

Population pharmacokinetic modelling of tramadol with application of the NPEM algorithms.

BACKGROUND AND OBJECTIVE: Although the kinetic behaviour of tramadol has been described, the present study is the first to our knowledge, to report specifically on the population pharmacokinetic modelling of tramadol hydrochloride. METHODS: The parametric Iterative Two-stage Bayesian Population Model (IT2B) program followed by the Non-parametric Expectation Maximization Population Model (NPEM2) program was used to determine population pharmacokinetic parameter values of tramadol in 138 postoperative orthopaedic Malaysian patients. All patients had received a 100 mg intravenous dose of tramadol, infused over 2-3 min, as their first postoperative analgesic. Blood was sampled at 0 min and subsequently at 15, 30 min, 1, 2, 4, 8, 16, 20 and 24 h for serum tramadol high-performance liquid chromatography analysis. RESULTS AND DISCUSSION: The one-compartmental model pharmacokinetic parameters--volume of distribution (Vd), elimination rate constant (kel) and the total clearance rates (ClT)--found were: mean Vd = 167.6 +/- 63.84 L; median Vd = 161.48 L; mean kel = 0.1241 +/- 0.056 h(-1); median kel = 0.1138 h(-1); ClT = 19.57 +/- 9.51 L/h; median ClT =18.12 L/h. The interindividual coefficient of variation of ClT (48.56%) was higher than that of Vd (38.09%), indicating the presence of other possible influencing factors on tramadol's ClT such as CYP2D6 polymorphism, gender and age. Overall, NPEM2 suggested more diversity in the population than did IT2B.

Adolescent↗
PubMed2004

Genetic polymorphism of CYP2D6 in patients with cardiovascular disease -- a cohort study.

BACKGROUND: Cardiovascular diseases are complex diseases that are influenced by both environmental and genetic factors. CYP2D6 found in the brain and the heart is involved in the metabolism of many environmental and some endogenous substances and neurotransmitters responsible for maintaining homeostasis. This raises an interesting hypothesis that it may have a role in the development of or protection against cardiovascular diseases. OBJECTIVE: To study the distribution of genotypes of CYP2D6 among patients with cardiovascular diseases in Malaysia. METHOD: We obtained DNA from 128 patients who were followed up for cardiovascular diseases. Polymerase chain reaction-based methods were used to determine common CYP2D6 alleles. RESULTS: One hundred and twenty-eight patients were enrolled. Most of the patients also had concurrent illnesses. Eleven genotypes were identified in the patients and 41% carried CYP2D6*1/*10. The second most common genotype was homozygous for the wild type gene, followed by homozygous CYP2D6*10/*10 at 14.48 %. A small percentage of the patients were heterozygous CYP2D6*1/*4. One patient was genotyped homozygous CYP2D6*4/*4 predicting a poor metabolizer prevalence of 0.78% (95% CI +/- 1.52%). Analysis using Hardy-Weinberg equilibrium showed that all of the gnotypes were consistent with equilibrium except for CYP2D6*1/*10 (chi(2); P < 0.05). CONCLUSION: Our study suggests a possible involvement of CYP2D6 genotypes in cardiovascular system diseases, which need to be validated by further studies.

Adult↗
PubMed2003

Standard CYP2D6 genotyping procedures fail for the CYP2D6*5 and duplication alleles when hair roots are used as a source of DNA.

BACKGROUND: Hair roots provide a useful alternative to blood as a source of DNA for genotyping. Besides simple and non-invasive collections, the DNA extraction step is also easy to perform and is fast. The aim of our study is to determine if hair roots can be used to genotype all of the common CYP2D6 alleles for routine screening purposes. METHOD: The study complies with the Declaration of Helsinki. After obtaining informed consents, both blood and hair samples were collected from 92 patients for genotyping of the CYP2D6 gene. PCR was used to detect the following mutations: CYP2D6*1, *3, *4, *5, *9, *10, *17 and duplication gene. The results were compared where hair roots and blood were used as templates for DNA respectively. RESULTS: When blood was used as a source of DNA for genotyping, all of the investigated CYP2D6 alleles were successfully amplified. However, with hair roots, the genes with the larger fragment sizes: CYP2D6*5 and the duplication gene could not be amplified and the bands of other alleles investigated were faint when visualized under UV light. CONCLUSIONS: DNA extraction from hair roots and leucocytes yielded similar results but the DNA extracted from hair roots did not allow successful amplification of the longer genes such as the CYP2D6*5 and the duplication gene.

Alleles↗
PubMed2003

A simple method for the detection of CYP2C9 polymorphisms: nested allele-specific multiplex polymerase chain reaction.

BACKGROUND: Cytochrome P4502C9 (CYP2C9), a principle drug-metabolizing enzyme is polymorphic in humans and is responsible for important pharmacokinetic and pharmacodynamic variations of CYP2C9 substrates. We developed an allele-specific multiplex polymerase chain reaction (PCR) method for the detection of common CYP2C9 alleles. METHOD: Genomic DNA was extracted from blood obtained from 40 unrelated healthy Malaysian Indian volunteers. The DNA was subjected to a first PCR that was used to amplify both exons 3 and 7 simultaneously in one reaction tube and a second PCR that was used to detect the polymorphic sites of CYP2C9 alleles using allele-specific primers. Sequencing was performed to validate the test results. RESULTS: We were successful in amplifying the fragments of interest from the DNA samples. The method was also reproducible and specific. The amplified sequences showed 100% homology to CYP2C9 sequence. CONCLUSION: This is the first nested allele-specific multiplex PCR method reported to allow for the simultaneously detection of five CYP2C9 alleles.

Alleles↗
PubMed2003

Genetic polymorphism of CYP2D6 in Chinese subjects in Malaysia.

BACKGROUND: Although Malaysian Chinese share an origin with the mainland Chinese, their evolution has been influenced by intermarriages. With a gene such as CYP2D6, which is highly polymorphic, it is expected that the Malaysian Chinese would exhibit a polymorphism profile different from those of the Chinese populations in other geographical locations. OBJECTIVE: To study the genotype distribution of CYP2D6 among the Chinese people in Malaysia. METHOD: We obtained DNA from 236 Chinese individuals in Malaysia and used PCR-based methods to identify any common CYP2D6 alleles. RESULTS: A total of 236 subjects were enrolled and were successfully genotyped. Malaysian Chinese were relatively heterogeneous in terms of their CYP2D6 genotypes with nine genotypes recorded. CYP2D6*4, *5, *9, *10 and *17 were detected with the most common genotype being *1/*10. No subject had genotypes that predicted poor metabolic activity. However, 40% showed genotypes (e.g. CYP2D6*10/*10, *17, *4 and *9 and *9/*9) that predicted an intermediate metabolizer phenotype. Another subject carried the defective CYP2D6*17 allele and six carried the defective CYP2D6*9 allele. Both these alleles have not been reported in other earlier Chinese studies. CONCLUSION: This study revealed that, in terms of CYP2D6 polymorphism, Malaysian Chinese were a heterogeneous group of people. Although sharing some similarities with other Orientals, they also seemed to have some notable differences. The alleles CYP2D6*4, *5, *9, *10 and *17 were all detected. CYP2D6*3 was however absent.

Adolescent↗
PubMed2002

Correlation of tramadol pharmacokinetics and CYP2D6*10 genotype in Malaysian subjects.

The aim of the present study is to investigate the influence of the CYP2D6*10 allele on the disposition of tramadol hydrochloride in Malaysian subjects. A single dose of 100 mg tramadol was given intravenously to 30 healthy orthopaedic patients undergoing various elective surgeries. After having obtained written informed consents, patients were genotyped for CYP2D6*10: the most common CYP2D6 allele among Asians by means of allele-specific polymerase chain reaction. The presence of other mutations (CYP2D6*1, *3, *4, *5, *9 and *17) was also investigated. Tramadol was extracted from 1 ml serum with an n-hexane: ethylacetate combination (4:1) after alkalinisation with ammonia (pH 10.6). Serum concentrations were measured by means of high-performance liquid chromatography. The pharmacokinetics of tramadol was studied during the 24 h after the dose. As among other Asians, the allele frequency for CYP2D6*10 among Malaysians was high (0.43). Subjects who were homozygous for CYP2D6*10 had significantly (P=0.046) longer mean serum half-life of tramadol than subjects of the normal or the heterozygous group (Kruskal-Wallis test). When patients were screened for the presence of other alleles, the pharmacokinetic parameter values were better explained. CYP2D6 activity may play a main role in determining tramadol pharmacokinetics. The CYP2D6*10 allele particularly was associated with higher serum levels of tramadol compared with the CYP2D6*1 allele. However, genotyping for CYP2D6*10 alone is not sufficient to explain tramadol disposition.

Adolescent↗
PubMed2002

Method development and validation of a high-performance liquid chromatographic method for tramadol in human plasma using liquid-liquid extraction.

An HPLC system using a simple liquid-liquid extraction and HPLC with UV detection has been validated to determine tramadol concentration in human plasma. The method developed was selective and linear for concentrations ranging from 10 to 2000 ng/ml with average recovery of 98.63%. The limit of quantitation (LOQ) was 10 ng/ml and the percentage recovery of the internal standard phenacetin was 76.51%. The intra-day accuracy ranged from 87.55 to 105.99% and the inter-day accuracy, 93.44 to 98.43% for tramadol. Good precision (5.32 and 6.67% for intra- and inter-day, respectively) was obtained at LOQ. The method has been applied to determine tramadol concentrations in human plasma samples for a pharmacokinetic study.

Analgesics, Opioid↗
PubMed2002

Removal of iron and manganese by artificial destratification in a tropical climate (Upper Layang Reservoir, Malaysia).

Environmental monitoring was carried out at Upper Layang Reservoir situated in Masai, Johor, Malaysia. The study shows that thermal stratification and natural mixing of the water column do exist in the reservoir and the level of stratification varies at different times of the year. Artificial destratification via diffused air aeration techniques was employed at the reservoir for two months. The results show that thermal stratification was eliminated after a week of continuous aeration. The concentrations of iron and to a lesser extent manganese in the water column was also reduced during the aeration period.

Iron↗
PubMed2001

Comparison of safety and immunogenicity of a Vi polysaccharide typhoid vaccine with a whole-cell killed vaccine in Malaysian Air Force recruits.

OBJECTIVE: To carry out a comparative study of the safety and immunogenicity of Vi polysaccharide vaccine against whole-cell killed (WCK) typhoid vaccine. METHODS: The study was carried out on young adult recruits (aged 18-25 years) of the Malaysian Air Force. A total of 125 subjects received the Vi polysaccharide vaccine and 114 received the WCK vaccine. FINDINGS: The Vi vaccine was significantly less reactogenic than the WCK vaccine with regard to systemic and local reactions. Following administration of the Vi vaccine, seroconversion rates (defined as the percentage of subjects with a 4-fold rise of baseline antibody level) of 75.5% and 67% were observed at 2 weeks and 6 weeks, respectively, after immunization, compared with 25% and 31.3% among recipients of the WCK vaccine. Of the 110 Vi vaccinees with serological data, 21 (19%) had high, seroprotective, pre-immunization levels of anti-Vi antibodies (> or = 1 microgram/ml). The majority of subjects in this group came from a region in Malaysia which is known to have high typhoid endemicity. Interestingly, these antibody levels were boosted considerably following administration of vaccine at a level that was 5-fold higher than in subjects with low pre-immunization levels. In contrast, the seroconversion rates in those receiving the Vi vaccine were higher in subjects with low pre-immunization levels of anti-Vi antibodies (76-84%), compared to those with protective levels of > or = 1 microgram/ml prior to immunization (48-57%). CONCLUSIONS: The study reaffirms the safety and efficacy of the Vi polysaccharide vaccine and identifies a hitherto unrecognized advantage in its use, i.e. it is a potent immunogen that boosted considerably the protective antibody levels among a significant number of immunologically sensitized individuals living in typhoid-endemic regions.

Adolescent↗